Background: Portal vein embolization (PVE) is a well-established technique for inducing liver hypertrophy in the future liver remnant (FLR) before major hepatectomy. A frequently used method in bilobar disease is the two-stage hepatectomy (TSH) technique combined with PVE (TSH-PVE). A novel approach is PVE, followed by a one-stage hepatectomy (OSH), combining major hepatectomy with clearing of the FLR (PVE-OSH). This study aimed to compare FLR hypertrophy between these two strategies for induced liver hypertrophy.

Material/methods: Patients with bilobar colorectal liver metastases (CRLM) who underwent PVE from January 2013 to December 2021 were included in this retrospective, multicenter study. Aspects of hypertrophy of the FLR were compared between the groups.

Results: The study included 188 patients, 127 in the PVE-OSH group and 61 in the TSH-PVE group. There were no statistically significant differences between the two groups regarding FLR hypertrophy measured by absolute and relative growth, degree of hypertrophy or kinetic growth rate. No major complications were reported.

Discussion/conclusion: No differences in FLR hypertrophy were demonstrated between the two different treatment strategies of TSH-PVE or PVE-OSH. This supports PVE-OSH as a feasible treatment option that reduces the surgical burden for patients with advanced, bilobar CRLM disease.

Background

Surgery may be the only chance for curative treatment of liver tumors and ensuring long-term survival. The extent of major liver resection is limited by the volume of liver parenchyma remaining after surgery. When the remaining liver volume is too small, the patient is at risk of posthepatectomy liver failure, which is a highly feared complication after extensive hepatic resection. In attempts to avoid posthepatectomy liver failure, hypertrophy of the future liver remnant can be induced before surgery. The aim of this thesis is to provide new and/or greater insights, along with possible benefits, problems and limitations, of the materials, methods, and measurements used for portal vein embolization and associated techniques for inducing liver hypertrophy.

Methods/materials

The studies reported in Papers I, III and IV were conducted as retrospective, multicenter cohort studies, and the outcomes after portal vein embolization were analyzed. Paper II presents a long-term follow-up survival analysis from a randomized controlled trial.

Results

Paper I: Compared with microparticles, the use of N-butyl-cyanoacrylate as an embolizing material results in a greater degree of hypertrophy and a higher resection rate, as well as lower radiation exposure, a shorter fluoroscopy time, and less contrast used, within the context of portal vein embolization.

Paper II: With a median follow-up time of almost eight years, no significant differences in long-term survival were detected between patients who underwent two-stage hepatectomy and patients who underwent associating liver partition and portal vein ligation for staged hepatectomy. In a multivariable analysis, the factors influencing long-term survival were extrahepatic disease, an increasing size of the largest liver metastasis, liver tumor-free status at the first follow-up, and a primary rectal tumor.

Paper III: Compared with portal vein embolization characterized by normal P-bilirubin levels, hyperbilirubinemia at the time of portal vein embolization did not result in decreased liver hypertrophy, as measured by absolute and relative growth, degree of hypertrophy, or kinetic growth rate. N-butyl-cyanoacrylate and elevated P-bilirubin levels were associated with increased liver hypertrophy.

Paper IV: Hypertrophy of the future liver remnant, as measured by absolute and relative growth, degree of hypertrophy, or kinetic growth rate, did not significantly differ between groups categorized by the timing of tumor clearance from the future liver remnant in relation to portal vein embolization.

Conclusions

The use of N-butyl-cyanoacrylate as an embolizing material is superior to the use of microparticles within the context of portal vein embolization.

Portal vein embolization is safe and exhibits a high success rate.

Two-stage hepatectomy and associating liver partition and portal vein ligation for staged hepatectomy yield similar long-term oncological outcomes in patients with advanced colorectal liver metastasis.

Hyperbilirubinemia at the time of portal vein embolization does not impair induced liver hypertrophy.

Similar results of liver hypertrophy are observed after portal vein embolization, regardless of whether the future liver remnant is cleared before the portal vein embolization procedure.

Behandling av levertumörer kan vara en stor klinisk utmaning med hög komplexitet, avancerade behandlingsmetoder, multipla, och ibland parallella behandlingar, samt föra med sig betydande risker för behandlingskomplikationer. För vissa levertumörer är kirurgi den enda möjligheten till bot och långtidsöverlevnad. Sedan de första rapporterade planerade leverkirurgiska fallen i slutet av 1800-talet har leverkirurgin tagit stora kliv framåt. Förståelsen för leverns anatomi och funktion har ökat, möjligheter till narkos och smärtlindring utvidgats och operationstekniska framsteg har lett till att allt större kirurgiska ingrepp blivit möjliga. Idag handlar stora leverkirurgiska operationer i allt större utsträckning om vad som blir kvar efter operationen, snarare än hur mycket av levern som är tekniskt möjlig att operera bort.

För att upprätthålla kroppens behov av en adekvat leverfunktion, och därmed undvika leversvikt efter operation, är det viktigt att tillräckligt mycket levervävnad finns kvar efter kirurgi. Genom att stimulera levertillväxt före ett större leverkirurgiskt ingrepp kan den del av levern som ska vara kvar i kroppen efter operationen (FLR, future liver remnant) växa till och uppnå en tillräcklig volym.

Olika tekniker och material har använts för att stimulera levertillväxt. Den vanligaste tekniken är portavensembolisering (PVE), som kan användas enskilt eller i kombination med andra behandlingar. De ingående studierna i den här avhandlingen har undersökt olika aspekter av inducerad levertillväxt och deras utfall.

Studie I undersökte materialval vid PVE och jämförde N-butylcyanoakrylat (NBCA; lim) med mikropartiklar.

Studie II studerade långtidsöverlevnad efter stimulerad levertillväxt och kirurgi, jämförande de två olika metoderna two-stage hepatectomy (TSH) och associating liver partition and portal vein ligation for staged hepatectomy (ALPPS).

Studie III undersökte om förhöjt P-bilirubin-värde vid tidpunkten för PVE har någon påverkan på levertillväxt efter PVE.

Studie IV jämförde huruvida invasiv behandling, eller att avstå invasiv behandling, av tumörer i den framtida kvarvarande levervävnaden har någon inverkan på tillväxten av FLR efter PVE.

Studie I, III och IV genomfördes som retrospektiva kohortstudier. Studie II är en analys av långtidsuppföljning från en tidigare randomiserad interventionsstudie.

Resultaten från Studie I visar att NBCA ger god tillväxt, och ur vissa aspekter, bättre tillväxt än mikropartiklar. Behandling med NBCA är snabbare, utsätter patienterna för lägre stråldos och använder en mindre kontrastmängd. Vidare är PVE en säker metod med låg komplikationsfrekvens och hög teknisk framgång vid utförandet.

I Studie II ses en likartad långtidsöverlevnad efter levertillväxt och kirurgisk behandling via metoderna TSH eller ALPPS.

Studie III påvisar att levertillväxten efter PVE inte blir sämre om patienterna i samband med PVE har ett förhöjt P-bilirubin samt att perkutan transhepatisk avlastning av gallvägarna i samband med PVE är möjligt med låg komplikationsfrekvens.

Från resultaten i Studie IV ses att invasiv behandling, eller att avstå från invasiv behandling, av tumörer i FLR före PVE, inte påverkar resultatet av levertillväxt i FLR efter PVE. Detta kan i förlängningen ge patienten möjlighet till färre antal invasiva behandlingar.

Objective: The objective of this study was to evaluate the long-term oncological outcomes of patients with colorectal liver metastasis (CRLM) randomized for associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) or 2-stage hepatectomy (TSH).

Introduction: For advanced CRLM, TSH or ALPPS may be needed for tumor freedom. The randomized, controlled, multicenter trial LIGRO showed an increased resection rate in patients who underwent ALPPS but no difference in morbidity or mortality. The 2-year survival analysis revealed better overall survival in the ALPPS group. Here, the long-term survival analysis from the LIGRO trial is reported.

Methods: In the LIGRO trial, 100 patients were randomized to TSH or ALPPS, with the option of rescue ALPPS if insufficient growth was found after the initial step of TSH. Patients were enrolled between June 2014 and August 2016. Follow-up data for this study were collected between November 2022 and February 2023.

Results: In total, 16 patients were alive at the end of the follow-up period. The estimated median follow-up time was 93 months. Estimated median overall survival times were 45 months in the ALPPS group and 27 months in the TSH group (P = 0.057), with 5-year survival rates of 31% and 20%, respectively. Positive prognostic factors were liver tumor-free status at the first follow-up and rectal primary tumor. Negative prognostic factors were extrahepatic disease and increasing CLRM size.

Conclusion: Liver tumor-free status is a predictor of long-term survival, along with extrahepatic disease, large CRLM size, and rectal primary tumor. Survival did not significantly differ between patients treated with ALPPS or TSH.